This Phase I clinical trial to test the safety, tolerability, and pharmacokinetics of ABT-627 for patients with advanced prostate cancer (PCA) and other refractory adenocarcinomas opened to accrual in July 1997. Tumor response and changes in tumor markers are evaluated. This is a dose escalation study of ABT-627 given orally each day for 28 days, followed by a week break. If there is evidence of clinical benefit, patients may continue to receive ABT-627 therapy. Nineteen patients have been enrolled across 6 dose levels (10,20,30,45,60, 75 mg/day). The cohort (18 males, 1 female) is made up of 14 patients with PCA, 2 with renal cell cancer, 2 with colon cancer, and 1 with lung cancer. Two patients are not evaluable because of early withdrawal secondary to disease progression as evidenced by cord compression. Toxicity has been minimal, with one patient experiencing a short-lived Grade 2 headache at 20 mg/day and one other patient with a Grade 3 headache for 4-5 days. Nasal congestion is the most frequent complaint. No hematologic, hepatic, or renal toxicity has been noted in the treated patients. Early pharmacokinetics are consistent with those obtained from healthy volunteers. The agent has a half-life of nearly 25 hours. Three patients with narcotic requiring pain had improvement in their pain with either a reduction in pain ratings or a decrease in narcotic use (Dose levels 10, 20, 30 mg/day) during the study period. One patient in this small cohort had a PSA decline < 50%, with the remaining PCA patients having PSA stabilization or minor declines. Of the 19 patients, 4 remain on study, 2 were withdrawn early, 4 patients progressed after 28 days of therapy, and 9 patients received therapy on the extension trial. Accrual continues to go exceedingly well. In summary, ABT-627, an ETA endothelin-receptor antagonist, is well tolerated in patients with advanced adenocarcinoma. Early PSA responses in the patients with prostate cancer and improvement in bone pain with a concomitant decrease in narcotic use is encouraging. Phase II studies with this agent are underway at this institution and other centers nationally and internationally. This Phase I trial laid the foundation for this accelerated program of drug development.